Amino acids SAMP

During our investigations on asymmetric C—C bond formation reactions via conjugate addition of SAMP hydrazones to various a,(3-unsaturated Michael acceptors, it occurred to us to use the chiral hydrazine auxiliary S AM P as a nitrogen nucleophile and a chiral equivalent of ammonia in aza-Michael additions. Thus, we developed diastereo- and enantioselective 1,4-additions for the synthesis of P-amino acids and P-aminosulfonates [14, 15]. 

Many chiral auxiliaries are derived from 1,2-amino alcohols.7 These include oxazolidinones (l),7-9 oxazolines (2),10 11 bis-oxazolines (3),1213 oxazinones (4),14 and oxazaborolidines (5).15-17 Even the 1,2-amino alcohol itself can be used as a chiral auxiliary.18-22 Other chiral auxiliaries examples include camphorsultams (6),23 piperazinediones (7),24 SAMP [(S)-l-amino-2-methoxy-methylpyrrolidine] (8) and RAMP (ent-8),25 chiral boranes such as isopinocampheylborane (9),26 and tartaric acid esters (10). For examples of terpenes as chiral auxiliaries, see Chapter 5. Some of these auxiliaries have been used as ligands in reagents (e.g., Chapters 17 and 24), such as 3 and 5, whereas others have only been used at laboratory scale (e.g., 6 and 7). It should be noted that some auxiliaries may be used to synthesize starting materials, such as an unnatural amino acid, for a drug synthesis, and these may not have been reported in the primary literature. 

The synthetic utility of the SAMP/RAMP hydrazone method is demonstrated in particular in the stereoselective alkylation of aldehyde and ketone SAMP/RAMP hydrazones. A great number of natural products have been synthesized using this method, like the principal alarm pheromone of the leaf cutting ant Atta texana (eq 1), the C(l)-C(15) segment of FK 506 (eq 2) the amino acid MeBMT (eq 3), and (-)-methyl kolavenate (eq 4). ... 

The basic concept, although most likely not the detailed mechanism, of the Enders asymmetric induction follows from the chelation-controlled asymmetric alkylation of imine anions introduced by Meyers and Whitesell. The hydrazones derived from either the (5)- or the (/ )-enantiomer of iV-amino-2-methoxymethylpyrrolidine (SAMP and RAMP, derived from the amino acid proline) can be converted to anions that undergo reaction with a variety of electrophiles. After hydrolysis of the product hydrazones, the alkylated ketones can be obtained with good to excellent levels of optical purity (Scheme 19). 

Enders, D., Bettray, W., Schankat, J., Wiedemann, J. Diastereo- and enantioselective synthesis of P-amino acids via SAMP hydrazones and hetero Michael addition using TMS-SAMP as a chiral equivalent of ammonia. Enantioselective Synthesis of/T-Amino Acids 1997,187-210. 

The asymmetric Strecker reaction Chiral Enolates from Imines of Aldehydes SAMP and RAMP Chiral Enolates from Amino Acids... 

The Oppolzer sultam 35-1 (Scheme 35, reaction (101) [84] reacts with even higher stereoselectivies and is easier to remove. The main domains of the Oppolzer sultam are conjugate 1,4-additions or simple double bond additions [Scheme 35, reactions (102) and (103)] [85], which show diastereoselectivities of >95% in most cases. Scheme 36 presents examples of persistent, restorable and selfimmolative auxiliaries which are all based on amino acids or amino alcohols, finders RAMP-SAMP [86] is attached to ketones or aldehydes in form of a hydrazone 36-1 which is used for highly stereoselective electrophilic a-alkyla-tions. After the reaction the auxihary is removed via ozonolysis which generates the nitrosamine 36-2 first. In an ensuing step this is reduced to the original auxiliary. In Schollkopf s bislactim ether alkylations [Scheme 36, reaction (105)]... 

The designation chiral pool was introduced to denote an available source of enantiomerically pure natural products. These include the (5)-amino acids, as well as (iS)-lactic acid, (5)-malic acid, (RJl)-tartaric acid and / -D-glucose. How the knowledge of their chirality can be utilized for asymmetric syntheses is demonstrated by an example of the chiral auxiliaries S) and (i )-l-amino-2-(methoxymethyl)pyrrolidine developed by Enders and abbreviated as SAMP (2) and RAMP [61]. They are synthesized from (5)- or (R)-proline in several steps [62]. The enantioselective synthesis of the insect pheromone (5)-4-methylheptan-3-one 8 by alkylation of pentan-3-one 1 serves as an example for the use of these chiral auxiliaries ... 

Scheme 25. Efficient enantioselective synthesis of p-amino acids.Asynunetric hetero Michael additions using SAMP as a chiral ammonia equivalent...

Komatsu M, Ueda Y, Hiramatsu M. Different changes in concentrations of monoamines and their metabolites and amino acids in various brain regions by the herbal medicine/Toki-Shakuyaku-San between female and male senescence-accelerated mice (SAMPS). Neurochem Res 1999 24 825-831. 

The preparation of a chiral bicyclic hydrazine, (15,35,5S)-2-amino-3-methoxymethyl-2-azabi-cyclo[3.3.0]octane (SAMBO, 3), was reported32 in 1990. (12 S, 31 S,51 5 )-2-Azabicyclo[3.3.0]-octane-3-carboxylic acid was resolved into its enantiomers. The (lS ,35,55)-enantiomer was converted to the chiral hydrazine 3 in six steps, utilizing Hofmann degradation, which is also employed in the preparation of SAMP. 

Having the electrophile 95 to hand, the synthesis proceeded by metallation of the SAMP hydrazone 96 followed by alkylation with the iodide affording the a-alkylated hydrazone 97 with diastereomeric excess de = 9S% (Scheme 1.2.21). The removal of the auxiliary proceeded smoothly with oxalic acid, leading to 98 in good yield (80%, two steps) and no epimerization without deprotection of the amino group. 

An efficient asymmetric synthesis of the 3-substituted /3-sultams 163 has been reported. The key step of the synthesis is the Lewis acid-catalyzed aza-Michael addition of the enantiopure hydrazines (A)-l-amino-2-methoxy-methylpyrrolidine (SAMP) or CR,l ,l )-2-amino-3-methoxymethyl-2-azabicyclo[3.3.0]octane (RAMBO) to the alke-nylsulfonyl sulfonates 176. /3-Hydrazino sulfonates were obtained in good yield and excellent enantioselectivity. Cleavage of the sulfonates followed by chlorination resulted in the corresponding sulfonyl chlorides 177. The (A)-3-substituted /3-sultams 163 have been obtained in moderate to good yields and high enantioselectivity over two steps, an acidic N-deprotection followed by in situ cyclization promoted by triethylamine (Scheme 55) <2002TL5109, 2003S1856>. 

This method was recently used in the synthesis of different natural products, like the ladybug defence alkaloid harmonine, a- and p-amino acetals and acids (eq 14), and both enantiomers of the hemlock alkaloid coniine, utilizing the nucleophilic 1,2-addition of organolithium and -lanthanoid reagents to SAMP/RAMP hydrazones. 

Amino-2-methoxymethyl pyrrolidine (SAMP) was prepared from L-proline according to a literature procedure. The synthesis began with the reaction of SAMP and the commercially available 4-chlorobutyric acid chloride (66) (Scheme 19). Treatment of the lo-chlorobutyro-hydrazide (67) with AgBp4 resulted in butyrolactone-SAMP hydrazone... 

Commercial (S)- and (R)-1 -amino-2-methoxypyrrolidines (SAMP and RAMP) can be synthesized from either prolines or glutamic acids. They are widely used for the stereoselective a-alkylation of aldehydes. One first forms the hydrazone with SAMP or RAMP and then alkylates in the presence of lithiu-mamide at low temperature. The optical purity is usually in the order of 90%, but enantiomeric excesses of 95% may also be obtained with large alkylbromides (Scheme 9.4.14) (Coppola and Schuster, 1987). 

Alkylation of lithiated hydrazones forms the basis of an efficient method for the asymmetric alkylation of aldehydes and ketones, using the optically active hydrazines (5)-l-amino-2-(methoxymethyl)pyrroUdine (SAMP) 59 and its enantiomer (RAMP) as chiral auxiliaries. Deprotonation of the optically active hydra-zones, alkylation and removal of the chiral auxiliary under mild conditions (ozonol-ysis or acid hydrolysis of the A-methyl salt) gives the alkylated aldehyde or ketone with, generally, greater than 95% optical purity. This procedure has been exploited in the asymmetric synthesis of several natural products. Thus, (S)-4-methyl-3-heptanone, the principal alarm pheromone of the leaf-cutting ant Am texana, was prepared from 3-pentanone in very high optical purity as shown in Scheme 1.74. 

Acylhydrazones, R CH=N-NHCOR , undergo stereoselective Mannich reactions with silyl ketene acetals to give j8-hydrazido esters, using activation by a chiral silicon Lewis acid. Alternatively, the use of silyl ketene imine gives a /3-hydrazido nitrile. Enantioselective (5)-l-amino-2-methoxymethylpyrrolidine (SAMP) hydrazone alkylation of aldehydes and ketones is the subject of a computational study, providing a useful screening method for possible new candidates. " ... 

Ort/io-substituted benzaldehyde complexes have been prepared in high enantiomeric purity (97% ee), and in a one-pot sequence, from an optically pure hydrazone derivative, readily available from -q -benzaldehyde chromium tricarbonyl and SAMP [(S)-l-amino-2-(methoxymethyl)pyrrolidine]. The novelty derives from the combined use of a diastereoselective orthoaddition reaction of an organolithium nucleophile and a hydride abstraction with a triphenylmethyl cation. The subsequent acid hydrolysis serves to remove the hydrazone group, thus liberating the aldehyde functionality (Scheme 6.13). 

Ketones can present a problem in specificity. Under basic conditions, they may react with two or more molecules of the electrophile to give a mixture of products. Furthermore, unsymmetric ketones may present a choice of two enolate sites so that control is necessary to direct to the desired one. Many alternatives have been developed for this problem. One solution is to incorporate a temporary group on one enolate site to render that site more acidic so that the electrophile will react there. The familiar p-ketoester reactions (acetoacetic ester synthesis) are widely used. For another alternative, the ketone is first converted to an imine (Section 6.2.3) or a dimethyl hydrazone, and the enolate of that derivative is used with electrophiles [28]. Stereospecificity of the addition is obtained by forming a derivative with (5)-l-amino-2-methoxymethyl-pyrrolidine (SAMP) as shown in Equation 7.15 [29]. Without derivati-zation, alkylation of unsymmetric ketones will occur mostly at the more substituted enolate site under reversible deprotonating conditions. Using a base such as EDA will give alkylation primarily at the least substituted enolate. 

In the late 1970s, Enders pioneered an elegant method for ketone and aldehyde alkylation involving the use of metalated chiral hydrazones [92, 93). Extensive studies with the (S)-l-amino-2-methoxymethylpyrrolidine (SAMP, 150, Scheme 3.24) auxiliary and its enantiomer RAMP established these as superb chiral auxiliaries with numerous applications. In a typical alkylation sequence, a RAMP/SAMP hydrazine is condensed with an aldehyde or a ketone to form the corresponding hydrazone, such as 152. This can subsequently be deprotonated and the resulting enolate trapped with a variety of electrophilic reagents including alkyl halides, aldehydes, Michael acceptors, silyl triflates, and disulfides. The RAMP/SAMP hydrazine auxiliary may be removed by acidic hydrolysis or ozonolysis to reveal the alkylated... 

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